2023
Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis
Mooring M, Yeung G, Luukkonen P, Liu S, Akbar M, Zhang G, Balogun O, Yu X, Mo R, Nejak-Bowen K, Poyurovsky M, Booth C, Konnikova L, Shulman G, Yimlamai D. Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis. Science Translational Medicine 2023, 15: eade3157. PMID: 37756381, PMCID: PMC10874639, DOI: 10.1126/scitranslmed.ade3157.Peer-Reviewed Original ResearchConceptsNonalcoholic steatohepatitisLiver inflammationNonalcoholic fatty liver diseaseProgression of NASHCysteine-rich angiogenic inducer 61Fatty liver diseaseLiver-specific knockout miceImproved glucose toleranceType 2 diabetesGlucose toleranceLiver diseaseNASH progressionProfibrotic macrophagesProinflammatory propertiesReduced fibrosisCardiovascular diseaseProfibrotic phenotypeFibrotic developmentKnockout miceNF-κBMetabolic diseasesNASH dietPDGFB expressionFibrosisProfibrotic program1558-P: The Mitochondrial Calcium Uniporter Regulates Hepatic Mitochondrial Oxidation and Intracellular Redox In Vivo
LAMOIA T, HUBBARD B, GUERRA M, GOODMAN R, NATHANSON M, SHULMAN G. 1558-P: The Mitochondrial Calcium Uniporter Regulates Hepatic Mitochondrial Oxidation and Intracellular Redox In Vivo. Diabetes 2023, 72 DOI: 10.2337/db23-1558-p.Peer-Reviewed Original ResearchNonalcoholic fatty liver diseaseHepatic mitochondrial oxidationMitochondrial calcium uniporterHepatocellular redox stateFatty liver diseaseEctopic lipid accumulationType 2 diabetesHepatic lipid contentNovel therapeutic targetMitochondrial oxidationHepatic triacylglycerol contentMitochondrial calcium influxMitochondrial redox ratioMitochondrial calciumKnockout mouse modelFortress BiotechMitochondrial fat oxidationNonalcoholic steatohepatitisLiver diseaseWT miceKO miceMetabolic dysfunctionCalcium uniporterCalcium influxMouse modelInhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis
Luukkonen P, Sakuma I, Gaspar R, Mooring M, Nasiri A, Kahn M, Zhang X, Zhang D, Sammalkorpi H, Penttilä A, Orho-Melander M, Arola J, Juuti A, Zhang X, Yimlamai D, Yki-Järvinen H, Petersen K, Shulman G. Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2217543120. PMID: 36669104, PMCID: PMC9942818, DOI: 10.1073/pnas.2217543120.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseLiver fibrosisLiver diseaseCommon chronic liver diseaseChronic liver diseaseFatty liver diseaseRisk of fibrosisDistinct mouse modelsPyrimidine catabolismNonalcoholic steatohepatitisMouse modelTherapeutic targetFibrosisDihydropyrimidine dehydrogenaseHuman liverA variantCommon variantsMetabolomics approachDiseaseMiceInhibitionCatabolismKnockdownSteatohepatitisGimeracil
2022
Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice
Bhat N, Narayanan A, Fathzadeh M, Kahn M, Zhang D, Goedeke L, Neogi A, Cardone RL, Kibbey RG, Fernandez-Hernando C, Ginsberg HN, Jain D, Shulman G, Mani A. Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. Journal Of Clinical Investigation 2022, 132: e153724. PMID: 34855620, PMCID: PMC8803348, DOI: 10.1172/jci153724.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisNonalcoholic steatohepatitisInsulin resistanceHepatic lipogenesisElevated de novo lipogenesisNonalcoholic fatty liver diseaseFatty liver diseaseLiver of patientsHepatic glycogen storageHigh-sucrose dietHepatic insulin resistanceFatty acid uptakeMetabolic syndromeLiver diseaseHepatic steatosisTriacylglycerol secretionNovo lipogenesisHepatic insulinTherapeutic targetImpaired activationAcid uptakeGlycogen storageMouse liverLiverLipogenesis
2021
Mechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 2021, 184: 2537-2564. PMID: 33989548, DOI: 10.1016/j.cell.2021.04.015.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseProgressive liver injuryFatty liver diseaseNonalcoholic steatohepatitisLiver diseaseLiver injuryHepatocellular carcinomaEffect of NAFLDHepatic stellate cell activationChronic liver diseaseBile acid toxicityStellate cell activationFibrosis progressionAdvanced subtypesMacrophage dysfunctionPathogenetic mechanismsCell activationHepatic glucoseLipid metabolismDisease consequencesDiseaseAcid toxicityCarcinomaInjuryMetabolic origin